tbuckley/cabot-search huggingface dataset:
Effect of delayed consolidation durvalumab and timing of treatment on survival outcomes in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT).
Authors: Samuel Xavier Stevens, Udit Nindra, Adel Shahnam, Victoria Jane Bray, Po Yee Yip, Tamiem Adam, Jenny HJ Lee, Michael J. Boyer, Adnan Nagrial, Steven Chuan-Hao Kao
Journal: Journal of Clinical Oncology (2022)

e18809 Background: Consolidation treatment with durvalumab following CRT is now standard of care for pts with unresectable stage III NSCLC. In PACIFIC, durvalumab was administered within 42 days of completing CRT. There has also been recent interest in whether the time-of-day immunotherapy is given impacts on outcomes. In practice, many pts experience delays to consolidation immunotherapy, and the timing of infusions is variable. We investigated the effect of treatment delays and time-of-treatment on survival outcomes in a real-world setting. Materials &amp; Methods: A retrospective observational study was conducted with patients treated with consolidation durvalumab following concurrent platinum-based CRT for unresectable stage III NSCLC in 6 centres across Sydney, Australia between January 2018 and September 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS) based on RECIST v1.1, from completion of radiotherapy. We collected treatment initiation and completion dates as well the administration time of durvalumab. In the time-of-treatment analysis, pts were stratified into median time of treatment either before or after 12.00pm. Survival was estimated using Kaplan-Meier and Cox-proportional hazard models. Results: 145 pts were included in the study. Median age was 67 years. 62.3% of pts were male, 84.9% were smokers, and 57.5% had adenocarcinoma. The median time between completion of CRT and commencement of durvalumab was 59 days (11-187 days). 71.2% (n = 102) of pts experienced a treatment delay. Over a median follow-up of 18.9 months, median PFS was 33.9 months in pts treated within 42 days of CRT and 25.6 months in pts treated beyond 42 days of CRT (HR 0.97; 95% CI 0.46-2.06; p = 0.815). Median OS was not reached in either group but no difference in OS was observed in the two cohorts (HR 1.07; 95% CI 0.39-2.96; p = 0.88). Median timing of treatment did not affect outcomes for either PFS (HR 1.07; 95% CI 0.50-1.71; p = 0.80) or OS (HR 1.01; 95% CI 0.44-2.31; p = 0.91). Conclusions: No difference in survival outcomes was seen between patients who had received durvalumab 42 days after CRT compared to within 42 days. The median timing of treatment did not appear to impact outcomes in our cohort.
A phase 1, safety and dose escalation study of BXQ-350, a nanovesicle formulation of saposin c, a modulator of sphingolipid metabolism, in patients with advanced solid malignancies.
Authors: Richard Charles Curry, Olivier Rixe, John Charles Morris, Robert Wesolowski, Emrullah Yilmaz, John L. Villano, Carolyn Muller, Trisha Michel Wise-Draper, Anne M. Noonan, Vinay K. Puduvalli, Gilles Tapolsky, Ray Takigiku
Journal: Journal of Clinical Oncology (2022)

e15059 Background: Bexion recently completed an all-comer Phase 1 clinical study of BXQ-350 in patients with advanced solid tumors including high grade gliomas to evaluate the safety profile and to determine the maximum tolerated- or biologically effective dose. BXQ-350 is a nanovesicle comprised of recombinantly expressed Saposin C (SapC) and dioleoylphosphatidylserine. SapC, a human protein encoded by the Psap gene, is an allosteric activator of several enzymes involved sphingolipid metabolism. Sphingolipids are bioactive signaling molecules implicated in multiple cellular processes including apoptosis and immune stimulation/inhibition. In nonclinical studies, BXQ-350 evidences broad anticancer activity, selectively inducing apoptosis of cancer cells by modulating sphingolipids (ceramides/S1P), and BXQ-350 acts synergistically with multiple classes of anticancer agents and treatments. Methods: In the trial (NTC02859857), performed at four US sites, BXQ-350 was administered intravenously for a minimum of 6 cycles over 28 weeks at escalating doses from 0.7 mg/kg up to 2.4 mg/kg. Multiple secondary parameters were included to characterize its pharmacokinetics, efficacy profile and identify potential biomarkers. Results: Results indicate that: i) BXQ-350 was safe and well-tolerated as no DLT was observed and an MTD was not reached; ii) treatment related adverse events leading to discontinuation were typical for this patient population and disease related; iii)* biomarker analyses suggest positive modulation of sphingolipid metabolism and stimulation of the immune system; iv)* surprisingly, some patients noted improvement of existing peripheral neuropathies. RANO or RECIST ver 1.1 criteria were used to evaluate tumor response: 13 patients reached Cycle 6 restaging (17% ORR); 8 patients (11.0% of evaluable patients) demonstrated progression free survival over more than 6 months; and 2 patients (a GBM and CRC patient) are still on study after 5 years. * subject of separate abstracts. Conclusions: In conclusion, BXQ-350 is a first-in-human and first-in-class novel biologic whose Phase 1 results suggest that it may have clinical utility either as a monotherapy or when combined with other targeted agents. Clinical trial information: 028559857.
Multifocal bronchial neuroendocrine tumor (bNET): A new clinical entity.
Authors: Nirosha D. Perera, Khalid Jazieh, Size Chen, Jason A. Wampfler, Thanyanan Reungwetwattana, Tucker F. Johnson, Anja Roden, Ping Yang, Dennis A. Wigle, Julian R. Molina
Journal: Journal of Clinical Oncology (2022)

9135 Background: Bronchial carcinoid (BC) is often categorized into multifocal (MBC) or solitary (SBC). MBC, excluding tumorlet and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, is considered a relatively uncommon subgroup of BC, with much of the MBC literature stemming from case reports/small series. Our study analyzes MBC among a large cohort of 569 patients with BC and argues for change to the current clinical understanding of MBC. We suggest using the term bronchial neuroendocrine tumor (bNET) to more accurately represent its cells of origin and move away from “carcinoid” (historically meaning “carcinoma-like”) and the outdated associated connotation that carcinoids all have a similar, benign clinical and biological behavior. Methods: Using the Mayo Clinic Epidemiology and Genetics of Lung Cancer Database with Institutional Review Board approval, we retrospectively reviewed 569 patients with bNET (204 males, 365 females) presenting to Mayo Clinic Rochester between 1/1997-12/2012. We used univariate and multivariate Cox regression analyses to evaluate factors affecting overall survival. Results: 80 patients (of 569, 14.1%) were diagnosed with multifocal (MbNET) and 489 with solitary (SbNET). Two-sided Fisher’s exact tests found that older age, female gender, never having smoked cigarettes, and tumorlets were associated with MbNET diagnosis. Family lung cancer history, histopathologic grading (pathology: typical vs. atypical), Ki67, and presence of syndromes (carcinoid, Cushing, and MEN1 syndromes) were similar between MbNET and SbNET groups. Most MbNET cases were stage III-IV at the time of diagnosis, while the majority of SbNET cases were stage I. 5-year OS (83%) and 5-year PFS (75%) of MbNET patients were higher than those of their SbNET counterparts (74% and 68%, respectively). Metastasis status was an independent prognostic factor of poor OS in SbNET (P&lt;0.001) but not in MbNET (P=0.71)(Table). Conclusions: Clinical, radiologic, and histopathologic characteristics and prognostic factors differed between SbNET and MbNET. MbNET arose as a new entity often with advanced stage disease, but good prognosis, which does not follow the NSCLC TNM staging system as in the 2009 NCCN guidelines (used during this study) or the updated 2021 NCCN guidelines which continue to stage lung carcinoid similarly to NSCLC. It may be beneficial to consider multifocal lung carcinoid instead as multifocal bNET, a new clinical entity, warranting a novel staging approach that more accurately reflects prognosis.[Table: see text]
Test performance and clinical validity of circulating tumor DNA (ctDNA) in predicting relapse in solid tumors treated with curative intent therapy.
Authors: Abhenil Mittal, Consolacion Molto, Faris Tamimi, Massimo Di Iorio, Laith Al-Showbaki, David W. Cescon, Eitan Amir
Journal: Journal of Clinical Oncology (2022)

3036 Background: Studies have explored the prognostic value of ctDNA in predicting relapse in solid tumors treated with curative intent. These studies have evaluated ctDNA at specific ‘landmark’ timepoint or over numerous ‘surveillance’ time points. However, variable results have led to uncertainty about the clinical validity of this tool. Here, we quantify the predictive and discriminatory accuracy of ctDNA and explore sources of heterogeneity at both landmark and surveillance time points across different tumor sites. Methods: A search of MEDLINE (host: PubMed) identified studies evaluating ctDNA after curative intent therapy in solid tumors. Odds ratios (OR) for disease recurrence at both landmark and surveillance time points for each study were calculated and pooled in a meta-analysis using the Peto method. Pooled sensitivity and specificity weighted by individual study inverse variance were estimated and meta-regression utilizing linear regression weighted by inverse variance was performed to explore associations between patient and tumor characteristics and the OR for disease recurrence. Results: Of 23 studies identified; 16 (750 patients) and 14 studies (853 patients) reported on landmark and surveillance time points respectively. The median time from completion of definitive therapy to landmark testing was 51.5 days (range 3-120). The pooled OR for recurrence at landmark was 22.22 (95% CI 14.82-33.30) and at surveillance was 27.51 (95% CI 19.1-39.63). The pooled sensitivity for ctDNA at landmark and surveillance time points were 59.9% and 73.2%. The corresponding specificities were 90.9% and 86.6%. Subgroup results are shown in the table. There was lower predictive accuracy with the use of tumor site specific panels, in patients receiving adjuvant chemotherapy and in lung cancer. Meta-regression showed that longer time to landmark and higher number of surveillance blood draws were associated with higher prognostic accuracy, as was a history of smoking. Conclusions: Although ctDNA at both landmark and surveillance time points shows high prognostic accuracy, it has low sensitivity, suboptimal specificity and therefore weak discriminatory accuracy to predict relapse in patients with solid tumors treated with curative intent. Testing methodology, time points and patient populations need to be optimized before it can be incorporated routinely in clinical practice.[Table: see text]
Impact of travel burden on overall survival in patients with lung cancer.
Authors: Dragomir Svetozarov Stoyanov, Ivan Tonev, Eleonora Dimitrova, Teodorika Panayotova, Rostislav Manev, Ivan Donev, Nikolay Conev
Journal: Journal of Clinical Oncology (2022)

6522 Background: High-volume specialized centers are more efficient at managing patients with lung cancer than low-volume centers. Centralization of cancer treatment has the potential to improve patient outcomes and quality of treatment. However, the growing centralization also increases patient’s travel burden (measured as travel distance or travel time) and may negatively impact access to specialist services. The aim of our study was to evaluate the potential impact of travel burden on clinical outcomes in patients with lung cancer. Methods: A retrospective analysis of a single Bulgarian center was performed. A total of 9240 lung cancer patients treated between 2005-2020 were included in the study. Travel distance between patients’ city of residence and the treating facility was calculated with an online tool to determine the shortest route for travel using the existing road network. The mean of travel time values for every workday of the week was calculated to control for daily changes in typical traffic. The probability of survival was estimated using the Kaplan-Meier method and differences in survival in each subgroup were evaluated with a log-rank test. Results: About one third of all included patients were living in the same city as the treating facility (n = 2746, 29.7%). The medians for travel distance and travel time were used to stratify patients into subgroups. According to travel distance the patients were grouped into three strata – same city, &lt; 50 km and ≥ 50 km. A cut-off of 60 min was used to stratify patients into three groups by travel time – same city, &lt; 60 min and ≥ 60 min. Overall survival in our patient population was significantly lower with increasing travel distance (p &lt; 0.001, Mantel-Cox log rank) and travel time (p &lt; 0.001, Mantel-Cox log rank). The 1-year OS rate according to travel distance was 27.1% in the same city group, 22.4% in &lt; 50 km group and 20.5% in ≥ 50 km group (p &lt; 0.001). The corresponding values for the 5-year OS rate were: 2.9%, 2.6% and 1.4% (p &lt; 0.001). Conclusions: In this retrospective study we discovered significant differences in overall survival of patients with lung cancer depending on travel distance and travel time to the treating oncological facility. Despite having similar clinical and pathological characteristics (age, sex, stage at initial diagnosis, histologic subtype), the median overall survival was significantly lower in those subgroups of patients with a higher travel burden. [Table: see text]
Clinicopathologic and molecular features associated with response to anti-HER2 therapy in endometrial cancer.
Authors: Sherry Shen, Weining Ma, Qin Zhou, Alexia Iasonos, Yanming Zhang, Dara S. Ross, Vicky Makker, Michael Herman Chui
Journal: Journal of Clinical Oncology (2022)

5584 Background: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States. Human epidermal growth factor 2 (HER2) overexpression or gene amplification occurs in 10-60% of EC. The addition of trastuzumab to carboplatin-paclitaxel chemotherapy improves survival in women with HER2-positive serous EC. However, criteria for assessment of HER2 status in EC are not standardized, and furthermore, intratumor heterogeneity may impact therapeutic efficacy. We aimed to identify factors associated with treatment response and survival outcomes in a retrospective cohort of ECs treated with anti-HER2 therapy. Methods: Patients with advanced/recurrent EC treated with trastuzumab or trastuzumab emtansine alone or in combination with chemotherapy from 2013-2021 at our institution were identified. Clinical and treatment information were retrieved from medical records. Central pathology review, HER2 immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) were performed. HER2 IHC was scored using modified ASCO/CAP 2007 guidelines for breast cancer. HER2 expression heterogeneity was defined as a 2-degree difference in staining intensity in ≥5% of tumor cells or discordant IHC score on different specimens. HER2 amplification (tumor/normal fold change) was also estimated from targeted next-generation sequencing (NGS). Best response was assessed by RECIST v1.1 as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), with clinical benefit defined as CR/PR/SD. Results: Among 39 patients included, median age was 69. Histologic subtypes included serous (n = 18, 46%), carcinosarcoma (n = 7, 18%), high-grade EC with ambiguous features (n = 13, 33%) and low-grade endometrioid carcinoma (n = 1, 3%). HER2 IHC results were 0 or 1+ (n = 2, 5%), 2+ (n = 17, 46%), 3+ (n = 18, 49%), with HER2 heterogeneity in 15 cases. By FISH, the HER2/CEP17 ratio was ≥2.0 in 34 (92%) and &lt; 2.0 in 3 (8%); HER2 copy number (CN) was ≥6.0 in 25 (68%) and &lt; 6.0 in 12 (32%). HER2 copy number ≥6.0 was significantly correlated with HER2 amplification by NGS ( p&lt; 0.001). 18 (49%) patients had a co-existing somatic PIK3CA mutation. Amongst parameters assessed, only higher level of HER2 amplification by NGS was significantly associated with clinical benefit ( p= 0.036). None of these features were associated with progression-free survival. Notably, 2 patients with IHC 0/1+ had PD and 1 patient with IHC 3+, but non-amplified by FISH, achieved PR. Conclusions: In our cohort of EC patients treated with anti-HER2 therapy, higher level of HER2 amplification was associated with clinical benefit. Further studies with larger sample sizes are needed to determine whether any additional characteristics are associated with treatment response and survival.
DELFI-L101: Development of a blood-based assay that evaluates cell-free DNA fragmentation patterns to detect lung cancer.
Authors: Peter J. Mazzone, Kyle Work, Victor E. Velculescu, Sonali Kotagiri, Lee Ming Sun, Daniel Dix, Debbie M Jakubowski, Alessandro Leal, Peter Brian Bach, Tara Maddala
Journal: Journal of Clinical Oncology (2022)

TPS3164 Background: Despite longstanding national recommendations, uptake of lung cancer screening in the US remains low. Barriers include access to lung cancer screening, costs, and concerns over potential harms like false-positives and radiation exposure. The DELFI technology evaluates fragmentation patterns of cfDNA using supervised machine learning to distinguish cancer from non-cancer [PMID30943338; 34417454; 31142840]. Methods: The DELFI-L101 is a case-control observational study (NCT04825834) prospectively enrolling at academic and community sites. Eligible participants (≥50 years of age) are individuals who currently smoke or previously smoked, with smoking histories of ≥20 pack-years. Individuals are ineligible if they had cancer treatment in the prior year or a history of hematologic malignancies or myelodysplasia. Cases are individuals with pathologically confirmed cancers (group A – lung, group C – non-lung). Controls are those without cancer (group B) as determined by low-dose computed tomography screening completed within 6 weeks of enrollment. Cases and controls are identified among enrollees from all participating sites. Total enrollment is estimated to be ̃2500 participants across all groups. Blood samples are collected at enrollment for DELFI analyses, which involves cfDNA isolation from plasma, low-coverage, whole-genome, next-generation sequencing, and machine learning methods. Clinical data (medical history, demographics, and diagnostic, surgery, imaging, and pathology reports, and/or other diagnostic information) are collected at enrollment and at 12 months post-enrollment. The primary objective is to train and test a classifier for the detection of lung cancer using the DELFI technology with other biomarkers and clinical features. Secondary objectives include the evaluation of classifiers to distinguish lung cancer from other cancers, modeling benefits and harms using performance estimates of these classifiers, and description of the analytical performance (eg, repeatability and reproducibility) of the DELFI technology and classifiers. The primary endpoint is the accuracy of lung cancer detection as measured by sensitivity, specificity, and the area under the receiver operating characteristic curve. Secondary endpoints include accuracy of tissue of origin classification, and adverse events associated with blood sample collection. The training and performance characterization of a DELFI classifier will further the development of an affordable, accessible, blood-based cancer detection tool with potential to overcome barriers to lung cancer screening. Clinical trial information: NCT04825834.
Evaluation of treatment patterns in patients with BRAF-mutant cutaneous melanoma in adjuvant setting in real practice.
Authors: Igor Samoylenko, Anna Stroganova, Ekaterina Shakhray, Kristina V. Orlova, Angelina Akhmetianova, Lev V. Demidov
Journal: Journal of Clinical Oncology (2022)

e21573 Background: Mutation in BRAF is a crucial biomarker for treatment choice in patient with locally advanced or metastatic melanoma. In patient with BRAF wild-type (WT) melanoma aPD1 is the preferred treatment regimen. In patients with BRAF V600 mutant melanoma combined targeted therapy (cTT) could also be chosen as adjuvant treatment, which significantly improves OS. Methods: We conducted a retrospective continuous study of all melanoma patients, who were tested for BRAF mutation by RT-PCR in 2020 (COIVD-19 pandemic year) in our institution and analyzed adjuvant therapy options they received. Patient demographics, mutational status, disease stage, treatment regimens and treatment outcomes were collected from electronic medical records. Results: Between January 2020 and December 2020, tumor samples from 297 pts were tested for BRAF mutations. The mean pts age was 58.2 years (95% CI 51.2 to 60.3) and 130 (43.7%) were male. BRAF mutations were detected in 147 (49.5%) patients. Most common mutation was V600E (140 out of 147 samples, 88.4%) and V600K (13 out of 147, 8.84%). We also found K601N, K601E, L597R and V600M mutations (in one sample each). Among 150 BRAF wild type samples 44 were also tested for NRAS mutations and in 13 (29.54%) pts NRAS mutations were detected: Q61R – in 6 (46.15%) pts, Q61L – in 2 (15.38%) pts, Q61K – in 3 (23.08%) pts, G12E – in 1 (7.69%) pt, and G12D - in 1 (7.69%) pt . Also among 150 BRAF wild type samples 56 were tested for KIT mutations and only one sample were found to harbour D186V mutation . Among BRAF-positive pts at time of the genetic test performed stage I CM had 11 (7.48%) out of 147 pts, stage II - 13 (8.84%) pts, stage III - 67 (45.57%) pts, and stage IV - 43 (29.25%) pts. In 13 (8.84%) pts stage could not be clearly identified. In most cases (32 out of 67, 47.76%) monotherapy with aPD1 was given as adjuvant treatment in stage III pts where as only 6 (8.95%) patients received cTT, 7 pts (10.41%) received IFN-alfa and 22 pts (32.84%) received no or were given with other treatment (Table). Median DFS did not differ significantly between treatment cohorts. Conclusions: In our retrospective study we found that among stage III BRAF-mutant patients monotherapy with aPD1 was the most common adjuvant treatment regimen. In some patients with stage III disease IFN-alfa is still given. More studies are needed to define best adjuvant treatment for BRAF mutant stage III melanoma pts.[Table: see text]